The long term goal of the Papillomavirus Research Unit of the University of Queensland is to study the immunobiology of HPV infection and hence develop vaccines that could be used: I) as a treatment for patients with HPV associated cervical cancer or precancer, or II) to prevent HPV infection, for all women at risk. The detailed aims of the present proposal are: 1) to create transgenic mouse models of HPV infection in which epithelial cells express HPV E6 and E7 proteins, using a number of strategies to avoid the lethal effects of these proteins on the developing embryo. Such mice should constitute an immunological model for HPV infected human cervical epithelium: peptides derived from HPV proteins will be presented by epithelial cells to the immune system without local inflammation. Mice immunologically naive with regard to HPV protein will be produced by induction of transgene expression in adult life, using an inducible binary transgene system, and by grafting transgenic skin to naive HPV transgene negative but otherwise syngeneic mice. Mice constitutively expressing the HPV transgene, and hence tolerant of it, will also be studied. 2) to test the effect of acquired immunity to HPV proteins on HPV E6 and E7 transgenic epithelium using our mouse models. Immunity will be induced by a number of vaccine strategies, including i) iscoms and HPV peptides, ii) baculovirus derived HPV proteins with 'Algammulin', iii) HPV peptides coupled to P3CSSS, iv) HPV recombinant adenoviruses, and v) HPV recombinant vaccinia viruses. 3) to determine, using in vitro assays for antigen specific cell mediated immunity, how the immune response to natural HPV infection in man compares with the vaccine induced immune response in mice, and the natural immune responses in naive and HPV tolerant transgenic mice. 4) to conduct a phase 1/2 clinical trial of the appropriate HPV16 E6 or E7 based vaccine in patients with advanced cervical cancer who have failed conventional therapy, and who have an HPV16 associated cancer expressing HPV16 E7 protein in tumor cells. The appropriate vaccine will be one producing immune responses which result in rejection of HPV transgenic epithelium in both naive and HPV tolerant mice.